This is competitive renewal of R01NS/HL36124-06, which has supported the development and continuation of the primary project in the Principal Investigator's laboratory. The investigators have developed and validated a clinically relevant outcome model of cardiac arrest and resuscitation in rats. The model is fully compatible with the use of the state-of-the-art magnetic resonance imaging (MRI) in order to (1) correlate long-term neuronal damage with post-resuscitation abnormalities in regional cerebral blood flow (rCBF), ion/water homeostasis as manifested in apparent diffusion coefficient (ADC), and cerebral energy metabolism, and (2) to evaluate the efficacy of different treatment strategies for cerebral protection and resuscitation after a well-controlled circulatory arrest. Research in the past four years has led to the conclusion that treatment based on energy metabolism and excitotoxicity mechanisms will inevitably fail if the vascular response to global ischemia and re-oxygenation is not addressed. For the next five years, the investigators will test the central hypothesis that intravascular goodness after resuscitation can be restored by intraparenchymal interventions. The research will focus on two closely related intraparenchymal events: angiogenesis and neurogenesis. Possible roles of the brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF) in alleviation of reperfusion injury wilt be investigated. BDNF and VEGF are chosen for their proven neuroprotective effects against ischerrfia, but their direct involvement in providing intraparenchymal treatment for reperfusion injury and protracted hypoperfusion has not been explored. The mechanisms of their protection against reperfusion injury are not fully understood. The synergistic link between these two factors, which underlies their choice for this project, is the recent finding that both factors seem to exert their neuroprotective effects via the extmcellular signal-related protein kinase (ERK) pathway. Methods for widespread gene delivery and transfer into the brain parenehyma have been developed by the investigators. The proposed new studies will combine gene therapy using recombinant adeno-associated viruses (rAAV) and stern cell therapy to accomplish the following three specific aims: Specific Aim #1: To investigate the therapeutic effects of the wide-spread over-expression of BDNF on the regional reperfusion recovery and reduction of neuronal loss in the selective vulnerability regions. Specific Aim #2: To achieve wide-spread gene delivery and over-expression of the main splice variants of VEGF (VEGF121 and VEGF165) in the rat brain to assist the post-resuscitation angiogenesis against hypoperfusion. Specific Aim #3: To devise a method for diffusive cerebral transplantation of multipotent stem cells and, in combination with BDNF and VEGF gene therapy, to study interaction of angiogenesis and neurogenesis. It is hoped that these specific investigations wilt pave the way to ultimately identifying the causal interaction between angiogenesis and neurogenesis after resuscitation from global ischemia.